Clinical Therapeutics/Volume 36, Number 2, 2014

Review Article

European Union Pediatric Legislation Jeopardizes Worldwide, Timely Future Advances in the Care of Children With Cancer Klaus Rose, MD, MS klausrose Consulting, Pediatric Drug Development & More, Riehen, Switzerland ABSTRACT Background: Diagnosis of childhood cancer is no longer an automatic death sentence, but it has not lost all of its horror. Drugs, surgery, radiation, and clinical trials have advanced our capacity to handle these cancers, but pediatric cancers still face challenges. Pediatric pharmaceutical legislation was introduced in the United States in 1997 and has triggered many clinical trials that have helped us better understand what drugs do to a child’s body and vice versa. Following the US precedence, the European Union introduced its own legislation. The US legislation was designed to generate additional pediatric data and balances between mandatory requirements and voluntary incentives. The EU legislation was deigned to mandate full registration of all new drugs for children whenever there is any potential pediatric use. Objective: The purpose of this article is to discuss unintended negative consequences of the legislation of the European Medicines Agency (EMA). Methods: We analyzed the effects of the EU pediatric legislation with respect to the history of the emergence of modern drugs, pediatric clinical pharmacology, and the development of drugs for pediatric malignancies. Results: No new drug can be registered in the European Union without a detailed pediatric investigation plan (PIP) approved by the EMA’s Pediatric Committee (PDCO). This has moved the discussion of the pediatric aspects of drug development to an earlier stage and has increased public awareness. It also has brought industry and pediatric oncologists closer together. However, in a review of 4100 PDCO PIP decisions in childhood Accepted for publication January 15, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.01.009 0149-2918/$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved.

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cancer, we found a lack of balance between the legitimate desire to include children in drug development and the common sense needed in the complex worlds of drug development and pediatric oncology. Many decisions appeared to have been based on both exaggerated assumptions about the frequency of childhood malignancies and the feasibility of the clinical trials proposed. Conclusions: Pharmaceutical companies are being forced into long-term commitments to clinical trials before efficacy in adults has been demonstrated. Pediatric clinical oncology trials are being driven by regulatory “tunnel vision” and not by therapeutic benevolence, epidemiologic data, or feasibility. As a result, children with cancer are being monopolized for PDCO-triggered, often unfeasible trials that are not always in their best interests and seldom produce useful therapies. Because clinical trials are global, this affects children with cancer worldwide. Until now, carefully worded concerns about these negative consequences have been published in specialty journals. It is time to start a broader debate on how to move forward. (Clin Ther. 2014;36:163–177) & 2014 Elsevier HS Journals, Inc. All rights reserved. Key words: childhood cancer treatments, clinical trial regulations, European Union, oncologic drug development, pediatric oncology, pediatric trials.

PEDIATRIC ONCOLOGY, NEW DRUGS, MODERN LABELS, AND OFF-LABEL USE OF DRUGS IN CHILDREN Cancer is quite different in children than in adults. Adult cancer is relatively frequent, whereas cancer in

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Clinical Therapeutics children is relatively rare, but both share 1 characteristic: they can kill. One hundred years ago, little could be done in either adults or children; but then, fewer adults reached the age at which most adult cancers develop. Adult cancer treatment evolved with the 3 pillars of surgery, radiation, and drug treatment. With some delay, these principles were also applied to children, with surprising results. Pritchard-Jones et al1 wrote that “childhood cancer is one of the success stories in the history of cancer treatment, with 5-year survival of 80% or more now being achieved in high income countries.” Modern pharmaceutical treatment evolved with the scientific revolution and with modern industry. Powerful drugs were synthesized, but it took 2 catastrophes—the sulfanilamide elixir in 1936 and thalidomide in 1961—to open the path to modern drug regulation in which the safety and efficacy of any drug must be proven in clinical and other trials.2 This signaled the advent of the modern label. Instead of allowing the manufacturer to claim whatever it would like to claim, modern labels reflect the outcomes of clinical and other trials. This also led to the pharmaceutical term off-label use—use of a drug in a therapeutic area or age group for which the drug is not registered. From 1961 on, most drugs in children were prescribed off-label.3 Cytotoxic and other agents have been developed and approved for adults since the 1950s. Learning how to use them in children took pediatric oncologists additional decades. They collaborated very early in international clinical trials.1 In the face of the potential death of a child, most parents agree to include the child in one or several clinical trials, so that participation in a clinical trial is today regarded as a “gold standard” in the treatment of cancer in children. Most treatment schemes for children with cancer, however, are still offlabel and probably will never be registered. The regulatory authorities did not play a major role in the revolution of pediatric oncology, but they also did not interfere.4 However, they played a key role in properly testing and licensing adult anticancer drugs. Most drugs today are developed by pharmaceutical companies, even if in some instances the original scientific discovery on which they are based comes from academia. Drug development has become a complex process from early discovery through preclinical and clinical development to marketing. This development is very expensive.5,6 The cost of a new drug is today estimated at over US $1

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billion. The chemical industry became the pharmaceutical industry and is today the health care industry or life sciences industry. The availability of powerful drugs predominantly for adults and their off-label use in children had several consequences, among them the evolution of pediatric clinical pharmacology as a subspecialty of clinical pharmacology.7,8 In the 1960s, pediatric disclaimers were introduced by drug manufacturers, largely to lessen the chances of being sued, emphasizing that the respective drug had not been specifically investigated in children. Because of this, Shirkey in 1968 referred to children as “therapeutic orphans” because children were excluded from the pharmaceutical drug-development progress.3

GLOBALIZATION OF PEDIATRIC CLINICAL RESEARCH Pediatric cancer is so rare that clinical trials have always required a larger recruitment area than just 1 hospital, 1 state, or even larger regions. In the United States, in 2009, 4 collaborative research groups that each conducted such trials merged voluntarily into the Children’s Oncology Group (COG).9 Pediatric clinical trials are performed today increasingly on a global basis,10,11 as are adult trials. There are several reasons for this, including the lack of availability of patients and research center costs, as well as a need for an appropriate physical and technical framework and a spirit that welcomes rather than discourages clinical research. A discouraging example of the latter is provided by the EU clinical trials directive of 2001.12 Introduced to establish an EU-wide framework for clinical research, the bureaucratic obstacles it introduced led to a onefourth reduction in the number of EU clinical trial applications and to an increase in costs.13 The 27 EU national bureaucracies found 27 different ways to interpret the directive, so in 2012, the EU commission published a proposal to replace it with a new regulation.13 A regulation in the European Union is hierarchically higher than a directive: it is immediately applicable in all EU member states, without the need for adaption into 28 national legislations (now 28 because Croatia joined the European Union in 2013).

CLINICAL PHARMACOLOGY AND PEDIATRIC PHARMACEUTICAL LEGISLATION In the United States, pediatric pharmaceutical legislation was first introduced as part of the US Food and Drug Administration’s (FDA) Modernization Act and

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K. Rose has been reauthorized repeatedly, the last time in 2012 within the FDA’s Safety and Innovation Act.3,14 This legislation offers a reward of a 6-month patent prolongation to pharmaceutical companies in exchange for voluntarily performing selected pediatric studies. The success of this legislation was cotriggered by the advances in clinical pharmacology and pediatric clinical pharmacology that had increasingly shown how different a child’s body is compared with an adult’s body, including how different absorption, distribution, metabolism, and excretion (ADME) of modern powerful medicines are in children compared with adults.7,8 A key feature of US legislation is that it was designed to provide clinicians additional, sciencebased information. Pediatric clinical pharmacologists in academia and industry, the American Academy of Pediatrics, and FDA officers were among the main driving forces that led to the US pediatric legislation. Drug development, as is everything that is complex and expensive, is also controversial. Like any other industry, the pharmaceutical industry is business driven. Adults have many diseases that the industry has successfully addressed in the past century. Along with the introduction of modern drug legislation came the need to prove safety and efficacy of new drugs with appropriate clinical trials. Both the industry and the medical community fought bitterly against the introduction of modern drug legislation when it was introduced in the United States in 1962 as part of the Kefauver-Harris amendments.2 However, if we look at the evolution of pharmaceutical industry since then, we see that this legislation was a key factor in pushing the then–chemical industry to become today’s multibillion dollar, multidimensional life sciences industry. In this evolution, money and shareholder values were priorities. Children’s health was considered only if children represented a market, such as with vaccines, growth hormones, lung surfactants, and antibiotics. Over decades, an imbalance evolved between the degree of sophistication in adult drug development and any focus on pediatric diseases. This was specifically true in oncology, largely because of the relative rarity of pediatric versus adult cancers. The voluntary pediatric study aspects of US pediatric legislation included in the FDA’s Modernization Act and subsequent legislation were later complemented by the mandatory Pediatric Research Equity Act (PREA) and subsequent legislation, which gave the FDA the authority to mandate pediatric studies.3,14

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However, this authority is restricted to the same disease as in adults; rare diseases were excluded from PREA requirements. The pediatric oncology community welcomed the US pediatric legislation because it was expected to result in better collaboration with the pharmaceutical industry and in earlier access to new drugs to be tested for potential therapeutic benefit in children. The voluntary US legislation offers patent prolongation in exchange for new data generated by adequate pediatric clinical trials. In essence, these pediatric clinical trials are financed by protecting the originator drugs against competition from generic drugs; in other words, the originator companies can charge the higher price for their products for a halfyear longer than a generic copy will cost once it has been introduced. The need for this “deal” came from the imbalance between the business-driven focus in adult drug development and less economically interesting areas, such as pediatric oncology. Of note, this very successful proposal was suggested by pediatric clinical pharmacologists working in the pharmaceutical industry. The outcome of this deal has been discussed in depth elsewhere.15 In the European Union, pediatric legislation came into force in 2007.3,16,17 Preceded by the US legislation, it was more ambitious. While pediatric discussion with the FDA will not block a new drug for adults, in the European Union, it can. Before a company can register a new drug in adults, it needs a PIP approved by the PDCO of the EMA. Without an approved PIP, the registration process for the new drug is blocked. The EMA PDCO is composed of 66 members and alternates, most of them representing the now 28 EU member states plus a few more associated countries (eg, Iceland), some representatives from another EMA committee, patient advocacy groups, and health care professionals. Within the EMA, a department of
30 people runs the administrative part of the PIP.18,19 The EU legislation has a greater emphasis than does the US legislation on mandatory pediatric studies, but it also offers a reward in the form of 6-month patent prolongation through a Summary Protection Certificate, a legal construct that reflects the lack of any EUwide patent law. Once a company has a Summary Protection Certificate, it can try to exchange it for patent prolongation in each of the 28 EU member states. Because the introduction of new drugs is the

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Clinical Therapeutics lifeblood of the research-based pharmaceutical industry, the threat to block new drugs is deadly serious. In the European Union, there is less balance between voluntary and mandatory pediatric development. The EU legislation created a voluntary incentive to develop pediatric formulations for drugs no longer protected by a patent, but this incentive (the Pediatric Use Marketing Authorization is of very limited financial benefit, as illustrated by the fact that it has, so far, only resulted in 1 newly registered pediatric formulation.20 The PIP should be submitted very early, at the end of human pharmacokinetic studies, that is, before anything is known about the efficacy of the drug. In contrast to the US legislation, a PIP must also obtained for drugs targeting rare and ultra-rare diseases must also obtain a PIP, even if the drug targets a disease that is found exclusively in children. The EU legislation expects a full pediatric registration, and its PIP should cover all potential future pediatric uses of the new drug. In the United States, mandatory pediatric trials cover only the same indication(s) as in adults. The European Union interprets an indication that a company is targeting as part of a “condition” and expects that whatever pediatric disease can be defined within this condition has to be addressed within the PIP.21 As a consequence, a drug company developing a medicine for postmenopausal osteoporosis must justify its focus on this type of osteoporosis. If this justification is not accepted by the EMA, they will expect the company to test the drug in another type of osteoporosis that also exist in children, such as steroid-induced osteoporosis.17 The company must “propose” pediatric investigation “measures,” such as technical formulations (eg, tablets vs liquids), juvenile-animal trials, clinical trials in a number of pediatric age groups and conditions, and others. This “proposal” is as voluntary as stopping your car when the police “asks” you to stop. If a company does not propose enough, it does not get a PIP, and registration of the drug for postmenopausal osteoporosis or any other use is blocked. The PIP procedure is cumbersome. Two months ahead of the PIP submission, a letter of intent is requested. When then the PIP is submitted, it must be validated by the EMA. If validation questions cannot be answered within the short deadline given, the company loses a month. After validation, the PIP has to be sent both electronically and as a physical CD-ROM to all PDCO members. A month after

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submission, the PDCO procedure starts. There are 2 procedure blocks of 60 days each, separated by a 3month clock stop, during which the company has to consider which PDCO requests should be modified in the PIP. The PDCO discusses the PIP 4 times, at days 30, 60, 90, and 120, and comes to a decision on day 120. On day 120, a company can request an “oral explanation” and either receives a PIP (“positive opinion”) or not (“negative opinion”).17–19 With a negative opinion, the company can ask for a reexamination by the same PDCO, or it can start a second PIP procedure, or it can sue the EMA at the European Court of Justice. The latter has been done unsuccessfully twice by 1 company.22,23

PEDIATRIC ONCOLOGY APPROACH AND DECISIONS BY THE EU PEDIATRIC COMMITTEE Pediatric malignancies are rare, and many are very rare. In addition, they are frequently subdivided into even rarer subgroups based on genetic and other characteristics that are being used to gradually improve treatment through the empirical, off-label testing of already-available medicines in clinical trials. Such systematic testing of off-label medicines has been tolerated by the regulatory authorities.4 The rarity of pediatric malignancies has important personnel implications for the testing of drugs. To become a pediatric oncologist, you study medicine first, then pediatric medicine, and then you specialize in pediatric oncology. Even then, you have just a general understanding of most tumors. To run a trial in pediatric clear cell carcinoma of the kidney, neuroblastoma, malignant germ cell tumors, rhabdomyosarcoma, or acute myeloid leukemia (AML), you must belong to a very small, highly specialized clinical community that knows almost everything about the specific target tumor. And, as is usual in medicine, even within this small group, there will be different opinions as to how and what to do clinically or in a trial.

EPIDEMIOLOGY AND THE PRACTICALITY OF PEDIATRIC TRIALS The EMA has on its Web site a list of class waivers, that is, a list of diseases that are declared to exist only in adults,24 but the EU legislation does not adequately address diseases that occur extremely rarely in children. For example, in 2008 the PDCO decided to revoke the class waiver for juvenile melanoma, because in its

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K. Rose opinion the disease frequency in adolescents “enables this population to be included in clinical trials.”25 The frequency of melanoma in adolescents was given by EMA as 1.7 per 100,000 population, referring to the statistics from the US Surveillance, Epidemiology, and End Results (SEER) Program26 in patients aged 15 to 19 years, as opposed to 0.1, 0.16, and 0.37 per 100,000 in the populations aged 1 to 5, 5 to 9, and 10 to 14 years.25 However, at least two fifths (40%) of the group aged 15 to 19 years (those aged 18–19 years) are adults per EU law, leaving
1.2 per 100,000 patients per year, but not all of these patients need systemic treatment of their melanoma. Wong et al27 wrote, “Five-year survival is currently nearly 100% for cases diagnosed in localized stages versus 82% for cases diagnosed as regional or distant stages.” Of all children with melanoma in the United States, as documented in SEER26,27 between 1973 and 2009, 77% had only localized disease.27 This reduces the number of adolescent patients eligible for systemic treatment to one fourth of those diagnosed with melanoma. Also, the likelihood that melanoma in adolescents is diagnosed early is much lower in India, China, and Africa,28,29 which decreases the number of patients globally who could be even approached to be in a trial. The EMA/PDCO frequency claim about adolescent melanoma is misleading. It is an overly enthusiastic and bizarre interpretation of the SEER statistics. Why was this not challenged before companies were asked to recruit pediatric melanoma patients in trials of new treatments? The evaluation of such claims requires an effective, knowledgeable, and practical interface between pediatrics, pharmacology, regulatory affairs, and other sciences; this interface appears to be missing in the current PDCO/PIP process. Only now, after the EU pediatric legislation has been in force for 47 years, are we starting to see the unintended negative consequences of not having such an interface, as illustrated by the PIPs generated because of this flawed interpretation of pediatric melanoma statistics.

MELANOMA PIPS As of January 2014, there were 5 melanoma PIPs on the EMA Web site (Table I).30–34 Two of these PIPs request efficacy demonstration in adolescents with metastasized melanoma by using a modeling-andsimulation approach; one asks for immunogenicity, one for “response” in patients with metastasized

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melanoma, and one for a comparison of 2 treatment schemes in adolescents and adults with resected highrisk melanoma. To what degree can any drug be shown to have efficacy or response in adolescent melanoma? The statistical power of these studies is extremely limited. In adults, there are enough patients to run double-blind studies comparing Z2 treatment schemes. In adult diseases that occur only extremely rarely in adolescents, inclusion of these patients into separate studies is unethical and does not help those patients. Adolescents with melanoma should have the right to participate in adult trials. The pharmaceutical industry has in the past, and in some cases continues to, wrongly excluded adolescents. Companies could be prohibited from excluding children or adolescents from trials, but is it ethical or even effective to force 5 companies to chase around the globe for adolescent melanoma patients in order to satisfy the EMA’s and PDCO’s feeling that they have done “something”? Forcing companies to recruit the rare pediatric melanoma patients into these trials also threatens to turn these patients into pediatric “hostages,” rather than just “therapeutic orphans” as coined by Shirkey in 1968,3 especially because none of these melanoma PIP studies are likely to ever be completed successfully. Yet even for studies that are extremely likely to be unsuccessful or even impossible to carry out, the operational work must be done, including protocol development, ethics committees’ approvals, opening of study centers, investigator identification and training, and budget negotiations, etc. These studies are ghost studies. Their only aim is to comply with PDCO requirements that have little to do with support of serious research of children with cancer. Obviously, the 5 melanoma companies decided that it was, from a business perspective, smarter to comply with these requirements than to sue the EMA. These melanoma PIPs were not submitted voluntarily; they are the result of coercion by the EMA, which otherwise could withhold these modern treatments from adult melanoma patients. Table I shows the summaries and timelines of these melanoma PIPs.

Standard PIP in AML (Acute Myeloid Leukemia) Another example of problems with the current process is illustrated by the standard PIP on AML, published by the EMA/PDCO in February 2013, which stated that “all subsets of the paediatric

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Drug Dabrafenib (EMEA-001147-PIP01110M01)

Ipilimumab (EMEA-000117-PIP02-10M02)

Mage-A3 recombinant protein (EMEA-001099-PIP02-11)

GSK1120212 (EMEA-001177-PIP01-11)

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RO 5185426 (EMEA-000978 -PIP01-10)

Description Development of an age-appropriate powder for oral suspension formulation.

Target Completion Date July 2019

Dose range/tolerability juvenile rat toxicity study to evaluate toxicokinetics and clinical observations in rats given dabrafenib or vehicle (control). Definitive juvenile rat toxicity study to evaluate toxicokinetics, clinical observations, laboratory parameters, and histopathology of major organs in rats given dabrafenib (at doses determined in measure 2) or vehicle (control). Juvenile rat renal toxicity study. OL, single agent, uncontrolled dose escalation to determine S, T, PK, & MTD of dabrafenib in children 1 mo to o18 y with advanced BRAF V600–mutant solid tumors. Evaluate relative bioavailability of dabrafenib pharmaceutical formulations in adults. Demonstrate that PK, PD, & E of dabrafenib in adolescents 12–o18 y with BRAF V600–mutant melanoma are similar to that in adults with BRAF V600–mutant melanoma, using a M & S approach for the purpose of extrapolation. IV study of pre- and postnatal development in cynomolgus monkeys with a 6-month postnatal evaluation. June 2018 OL dose escalation CT of IV-administered ipilimumab in 2–o18 y (and young adults to 21 y) with untreatable, refractory, or relapsed solid malignant tumors. OL MC single-arm CT of IV-administered ipilimumab in 12–o18 y with untreated or previously treated advanced/metastatic melanoma. OL R active-controlled study of adjuvant ipilimumab anti-CTLA4 therapy vs high-dose interferon α-2b in 12–o18 y (and adults) with resected high-risk melanoma. MAGE-A3 antigen expression in pediatric solid malignant tumors.

December 2019

OL, single-arm, uncontrolled trial to evaluate S & immunogenicity in 12–o18 y with resected MAGE-A3–positive melanoma. Develop an age-appropriate powder for oral solution formulation. October 2019 Juvenile rat toxicity study to evaluate toxicokinetics, clinical observations, laboratory parameters, and histopathology. OL, single-agent, dose-escalation trial to evaluate S, T, PK, & PD in children 1 mo to o18 y with relapsed or refractory solid malignant tumors. DB, R, controlled, parallel-group trial to evaluate S & E in children 1 mo to o18 y with solid malignant tumors with known or expected RAS, RAF, or MEK pathway activation. Relative bioavailability study in adults. Demonstrate that PK, PD, & E in adolescents 12–o18 y with BRAF V600–mutant melanoma are similar to those in adults with BRAF V600–mutant melanoma, using a M & S approach for the purpose of extrapolation of E. Develop a round-shaped 120-mg tablet with a maximum diameter o 10.5 mm. March 2017 OL, MC, single-arm trial to evaluate recommended dose, S, PK, & response in patients 12–o18 y with BRAF V600 mutation positive, nonresectable Stage IIIC or IV melanoma.

CT ¼ clinical trial; E ¼ efficacy; EMEA ¼ European Medicines Agency; M & S ¼ modeling and simulation; MC ¼ multicenter; MTD ¼ maximum tolerated dose; OL ¼ open-label; PD ¼ pharmacodynamics properties; PG ¼ parallel-group; PK ¼ pharmacokinetic properties; R ¼ randomized; S ¼ safety; T ¼ tolerability.

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Table I. Pediatric investigation plans for melanoma treatments.

K. Rose population with AML should be discussed in the PIP documentation and the PIP indication should target 2 or 3 of the following subsets, selected based on a scientific rationale for the medicine and with the objective to improve the overall outcome in AML.” Patient subsets with high unmet medical needs in AML include35:

 Patients with newly diagnosed high-risk AML: need

 

    



for a more efficacious treatment as part of a firstline induction regimen, in particular when there is a good rationale for use during first-line treatment, such as the individual disease biology (eg, FLT3 mutations with high allelic ratio) or the potential for reduction of toxicity Patients with AML resistant to first- or second-line induction treatment: need for an efficacious treatment as part of a re-induction regimen Patients at the time of diagnosis of relapse after hematopoietic stem cell transplantation/second or subsequent relapse: need for an efficacious treatment that is not overly toxic because they may have had high cumulative previous treatment exposure, likely including Z1 prior transplant procedure Patients with secondary AML: need for an efficacious treatment Patients at the time of diagnosis of early first relapse: need for a more efficacious treatment as part of a treatment regimen Patients at the time of diagnosis of first relapse (other than early): need for a more efficacious treatment as part of a treatment regimen Patients with APL: need for more tolerable treatment to be used during induction Patients with AML in Down syndrome: needs may exist, specifically for noncytotoxic or “targeted” medicines to reduce treatment toxicity; needs may be less in patients o1 year of age and in those with French-American-British classification M6 or M7, compared with other patients with AML in Down syndrome Patients with congenital or extramedullary AML

This list shows what happens when a regulatory institution with limited or no pharmaceutical experience tries to direct clinical drug development. Yes, many aspects of AML and its subpopulation are listed. However, the pediatric oncology study groups (eg, COG or the International Society of Paediatric Oncology) have special treatment arms and treatment windows for special subpopulations, such as patie-

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nts resistant to primary and secondary induction treatment. These time windows or study windows are used to investigate the therapeutic potential of new drugs, new treatment methods, or combinations thereof that are all designed to potentially provide direct benefit to the patients enrolled. The EMA/ PDCO standard AML PIP has the opposite focus: Each individual PIP is submitted by 1 company for its compound. The EMA makes the applying company “propose” a number of studies that should lead to the registration of the respective compound in AML (or one of the listed subgroups). Such a registration procedure makes sense in the adult population with high case numbers. An efficacy study in juvenile melanoma or subtypes of AML cannot follow the same logic. Imposed by an agency, it may make the agency feel that it has done “something” for patients with adolescent melanoma or subtypes of AML, but unfortunately, this “something” is not useful. To the contrary, it not only results in the incorrect prioritization of patients but also introduces disturbing market forces into a research area that has been well-covered in the past by the pediatric oncology research networks. The consequence of this standard PIP will be that companies will chase pediatric patients with one or the other subcharacteristic of AML around the globe. Project managers could even be tempted to induce treating physicians to include a patient into this or that commercial study rather than enroll him or her in an oncology network study. If commercial drug development research budgets are compared with the budgets of pediatric oncology treatment centers, it does not take a genius to imagine how a young, enthusiastic project manager might try to achieve the PDCO’s recruitment goals. Doing so would be completely logical within the manager’s personal goals but completely against the interest of the involved children. Through these PIPs, the EMA and PDCO have begun to impede the recruitment of children with AML into trials organized by pediatric oncology research networks. This is done through PIPs that they can threaten to refuse until “the applicant” (submitting company) “proposes” the studies that the EMA/PDCO wants done.

LEUKEMIA PIPS As of December 2013, 105 PIP decisions were found on the EMA Web site when PIP decisions were searched using the key word oncology.36 All

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Clinical Therapeutics documents that addressed PIPs for drugs that target leukemia were considered, except for those involving vorinastat (which is listed as having a PIP decision but has a “no pediatric development required” waiver). The remaining 10 leukemia PIP decisions are listed in Table II.37–46 A glance at Table II shows several challenges, the first of which is the time range for the completion of these trials (“deferral” is up to 2024, ie, 410 years into the future). These PIPs were discussed with the PDCO before proof-of-concept studies were completed, that is, before it is known whether the substance under development has any clinical efficacy. Second, it shows the horizon of the EMA/PDCO. This committee—composed of generalists, of whom most have worked most of their professional lives in a national regulatory agency, plus some pediatricians, of whom maybe 1 or 2 have any training in pediatric oncology—assumes the responsibility of deciding which compounds should be developed, in which diseases, and in which combinations during the next decade. The requested clinical trials, not surprisingly, follow a standard scheme: age-adapted pediatric formulations, a few studies in juvenile animals, dosefinding studies, and various Phase II and III studies, all aiming to register the drugs in the treatment of pediatric malignancies—as if there were enough patients for every single drug/studies combination. It is highly unlikely that the US FDA would ever attempt, let alone be successful in, proposing such a scheme.

Such a proposal by the FDA would have been met with a huge public outcry led by both by pediatric oncologists and patient groups. But the European Union is not the United States. PIPs are the outcome of a 1-year negotiation, at the end of which the EMA/PDCO can issue a negative opinion that could block registration of a new drug. Interestingly, the PDCO does not decide about registration; this is the responsibility of the Committee for Medicinal Products for Human Use. Companies (“the applicant”) have by now learned that they must continue to “propose” studies until their counterpart from the PDCO hints at a potential approval. The negotiation between applicant and EMA/PDCO is run by 3 representatives of the pediatric machinery: 1 EMA pediatric coordinator and 2 representatives of the PDCO (the rapporteur and the peer reviewer).17–19 Depending on the personality and the qualifications of the specific PDCO members, their suggestions and requests can be reasonable or less reasonable. Individual project managers in the pharmaceutical industry see their projects and little else. Confronted with the fact that their counterpart is both “judge and executioner,” managers are likely to simply follow their counterparts’ logic and keep adding study “proposals” until a potential agreement is hinted at. The final agreement is then discussed by the PDCO behind closed doors, with 1 opportunity for a clarification teleconference in the middle of the procedure and 1

Table II. Pediatric investigational plan decisions on leukemia treatments. Drug Dasatinib (EMEA-000567-PIP01-09-M04) Decitabine (EMEA-000555-PIP01-09-M04) Elacytarabine (EMEA-001121-PIP01-10) Imatinib (EMEA-000463-PIP01-08-M03) L-asparaginase (EMEA-000341-PIP02-09) Mercaptopurin (EMEA-000350-PIP01-08) Midostaurin (EMEA-000780-PIP01-09) Obinutuzumab (EMEA-001207-PIP01-11) Recombinant L-asparaginase (EMEA-000013-PIP01-07-M03) Volasertib (EMEA-000674-PIP02-11)

Indication

Deferral Until

Ph-positive ALL ALL AML ALL et al ALL ALL AML et al ALL et al ALL AML

June 2018 July 2021 September 2019 June 2011 December 2016 December 2009 December 2019 June 2024 November 2012 December 2023

ALL ¼ acute lymphatic leukemia; AML ¼ acute myeloid leukemia.

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K. Rose face-to-face “dialogue” of maybe 30 minutes on the last day of the PIP procedure (day 120). For a company, it is then a simple decision: accept whatever is asked for as long as the project is not totally blocked, or not. Although in the melanoma case even a medically untrained judge at the European Court of Justice might easily see the faults in the EMA/PDCO logic, the companies that develop new treatments for melanoma have decided to simply take the PIP route instead. Can we blame them? We have seen the scientific basis for the PDCO’s arguments regarding the epidemiology of adolescent melanoma. The scientific depth of other PDCO assumptions and decisions may be comparable, but all details are confidential. By looking at Table I, we see 1 decisive feature: If the number of children with AML were enough worldwide to run all of the listed safety and efficacy studies, every single PIP might be defendable, but it is not. The science of pediatric oncology developed with little involvement from regulatory authorities, and their patients’ survival results demonstrate how well these clinicians have done. Pediatric clinical oncology is now facing a threat from a rather unexpected source: the EMA and its PDCO/PIP process which is acting (pretending?) as if there is an unlimited patient pool and forcing companies to commit to clinical studies (even if only by “proposing” them!) that they know they will never be able to complete or recruit for. The PDCO does not see this as a problem because failure to complete studies need not block eventual registration. After 5 years of opening centers, getting approval from ethics committees/institutional review boards and recruiting an occasional patient here or there, the company (“the applicant”) can simply go back and report that recruitment failed. There is a form on the EMA Web site for companies to request PIP modifications,47 and there is also a specific question on the PIP application form that asks what the applicant will do if recruitment is lower than planned.48 Recruitment in pediatric clinical trials is known to almost always be below expectations. A standard answer frequently used by applicants who report slow enrollment is to merely open more study centers. But what are the unintended results of this approach? Failure to recruit adequate numbers of subjects means, at a minimum, that precious resources of both the pharmaceutical industry and pediatric oncologists were wasted on PDCO negotiations. In

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pediatric oncology, the pediatric discussion has deteriorated into Kafkaesque discussions with counterparts who are convinced, to remain with the example chosen above, that they must save the world’s adolescent melanoma patients by enforcing at least 5 melanoma PIPs, none of which will recruit the required number of patients within the deadline for the PIP decisions (Table I). Meanwhile, adolescent patients with melanoma who need systemic treatment will be given adult treatment schemes anyway. Perhaps pediatric patients should be warned against enrolling in any clinical study that simply cannot be successful, including those triggered by PIP requirements. What are these ghost studies good for? Have they not simply made children with cancer (and other children with rare diseases) therapeutic hostages? If so, is this justified, just to give some EMA or EU national regulatory authority employees the feeling that they have “done at least something” for children with various forms of cancer? And does the mere approval of these ghost studies not undermine the public trust in the need for, and reasonableness of, clinical trials in children with cancer?

ACADEMIC CRITICISM OF THE EU PEDIATRIC LEGISLATION The current attitude of pediatric oncologists toward the pharmaceutical industry is influenced by experiences from the past, when industry had little interest in pediatric oncology. The size of the pediatric market is indeed small compared with that of the adult market. Political pressure, especially over the past few decades, has somewhat modified industry’s behavior, but essentially the pharmaceutical industry remains a business like any other one. However, academics, who treat most pediatric oncology patients, and the industry, which develops and markets almost all oncology drugs used, must work together to improve pediatric cancer treatment. The EU pediatric legislation is having a negative effect on this relationship. Four academic assessments of the development of pediatric oncology treatments were recently published.1,4,28,49 Two of these papers openly criticize the EU’s pediatric clinical legislation,4,49 as does 1 paper from Peter Adamson, chair of the US COG.50 Sullivan et al4 ask: What is the best way to identify effective treatments for childhood cancers? In view of the complex and

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Clinical Therapeutics heterogeneous nature of these cancers, the trend in the past few years for industry to drive the development of clinical research plans contrasts with the need for broad research and development partnerships that can deal with complex biology and drug development. Companies are developing research plans to meet regulatory obligations related to the drugs that they are developing for adult cancers. This trend takes the primary responsibility for research direction away from the larger paediatric oncology community, and also tends towards the fragmentation of childhood cancer clinical research activities—as opposed to the cooperative, unified clinical research activities that are needed in view of the small numbers of children with specific cancer types. Thus, the long-term effects of this trend raise serious concerns. Sullivan et al see what companies are doing, but they do not mention that they are being coerced into doing so. In another paper, Vassal et al49 go even further: In the USA and Europe, a major unintended consequence of paediatric investigation plans is a delay in the initiation of early-phase clinical trials by companies. Paediatric investigation plans require review and approval of a complete development plan—sometimes including phase 3 trials— before any paediatric clinical data are available. Commitments to plan phase 3 and beyond before the drug has been tested in children are counterproductive because the early-phase clinical data determines whether a drug should be fully developed, and, if so, how. As a result, companies delay initiation of phase 1 investigation while trying to develop complex phase 3 development plans without key data and waiting for paediatric investigation plans to be approved. An overarching concern is that the incentives and requirements put in place generally happen in isolation, with each drug assessed independently. Thus, paediatric investigation plans for different compounds are approved for the same indication, and the feasibility of simultaneous drug trials in these rare-disease populations is disregarded. Prioritisation of clinical research studies by the paediatric oncology research community, including essential input from cooperative group programmes, is absent from the process… . What changes should be made to the US and EU regulations, and what guidance should be given to address limitations? A waiver should be issued on the basis of the mechanism of action or target of

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a new drug rather than the pathological adult indication… . Paediatric investigation plans should limit development proposals to phase 1 and 2 clinical research, and defer any discussion of phase 3 trials until the necessary early-phase paediatric data are available to inform such discussions. To identify requirements for industry, a more diseasecentred or target-centred approach rather than a drug-centred approach is needed. Finally, cooperation between the global childhood cancer community, regulatory agencies, and pharmaceutical companies should be pursued to prioritise new drug studies. Vassal et al then propose a biology/preclinical evaluation of the respective compound. But the efficacy of existing preclinical evaluation methods is limited. Furthermore, in Europe, in contrast to the United States, there is no institution funded by the public to do such investigations; such a service is offered in Europe by Innovative Therapies for Children with Cancer consortium.51 If adopted, the proposal by Vassal et al would give a bit more influence to the EU academics that are organized in Innovative Therapies for Children with Cancer. They could sell more services in the biology/preclinical evaluation of pediatric cancers, but this would not change the logic of the PIP, and it does not prevent all the disastrous, albeit unintended, consequences of the EU pediatric machinery.

FRAMEWORK OF DRUG DEVELOPMENT The EMA and its PDCO act in the belief that they help children with cancer and other malignancies. As long as they focus only on the observation of 1 individual PIP, some justification for their actions can be found, although this justification will be shallow, as explained earlier in the example of adolescent melanoma. There is a need to expand their focus to consider the combined, global effects of their individual PIP actions. There are 2 executive pillars to the EU pediatric legislation. The EMA carries the administrative part, such as validating PIPs, organizing PDCO meetings, publishing statistics on PIPs, organizing workshops on pediatric diseases, and maintaining the EMA Web site. The PDCO is predominantly composed of representatives of the EU member states, the majority being employees of national regulatory authorities. There are many medical doctors, of whom a few are

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K. Rose pediatricians; many pharmacists; and a few with other qualifications. The PDCO members are highly qualified, but they lack the special training and decadeslong experience as a pediatric oncologist you would expect from a pediatric oncologist you, as a parent, would trust to make decisions about the life of your child. Employees of regulatory agencies may think they are capable of setting priorities in drug development based on a public health view, but this is not their task. Regulatory agencies have to set a framework. Companies invest money and survive—or not. We may not like all of the products that are developed and sold or all of the decisions they make, but in a free society, regulatory agencies do not decide about good or bad “taste.” We see an increasing number of new drugs being developed against rare diseases, especially in the United States. The traditional large pharmaceutical companies are involved, as are relatively new types of companies with different backgrounds. Their funding comes from philanthropy, venture capital, patients and their parents, tax payers, or a mixture of these. Obviously, the laws of the free market allow for profits to be made from drugs developed for rare diseases, and that is good. It may not be as fast as desirable, but there is no better system. The newest FDA legislation (FDA Safety and Innovation Act) includes a provision to facilitate breakthrough therapies.52

THE WAY FORWARD IN THE EUROPEAN UNION The idea for an EU pediatric legislation was triggered by the US example. The desire to outperform the United States is not new in Europe. That good intentions do not necessarily lead to good results is not new in history. With the introduction of the first pediatric legislation in the United States in 1997 and then the EU legislation in 2007, there were high hopes that the power of industry-based research and development could successfully be turned against childhood diseases, including cancer. The EU pediatric legislation was the result of lengthy consultations with various stakeholders and their organizations. As usual, it reflects a number of influences, including different interests, different open and hidden agendas, different open and hidden opinions, and assumptions. One such assumption is that all off-label use is dangerous, which is in fact untrue.

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A drug used without registered dosing recommendations in children can be dangerous if given by a practitioner who does not know its side effects, does not know or consider its potential interaction with other drugs, and is not aware of the required types and levels of monitoring required for its use. But this is not the situation in pediatric oncology, even in Africa.29 In the hands of well-trained pediatric oncologists in cooperative pediatric oncology groups such as COG or the International Society of Paediatric Oncology, the drugs and drug combinations currently used for the treatment of children with cancer are the best that science and society can offer, with or without the blessing of regulatory authorities. Journalists, representatives from regulatory authorities, or others who claim that the unlicensed use of medicines in children is negative per se should be challenged. This claim should no longer be accepted or unquestioningly supported. Like so many other things in life, it depends on the specifics of the situation. There have been definite, positive effects of the EU pediatric legislation, including the fact that it has improved the acceptance of the need for pediatric clinical trials by the scientific, academic, and medical communities, as well as by legislators, pharmaceutical employees, patients, parents, and within the general public. However, there have also been some dangerous, unintended negative consequences, including, in particular, the development of drugs for pediatric cancer patients, which, if not corrected, have the potential to undermine the positive achievements of this legislation as well as the public trust they have generated. The EU pediatric legislation will be revised in 2018. Special consideration needs to be given, within the general legislation-renewal debate, to the unintended problems created in pediatric oncology. At present, the general perception of the EMA and its PDCO about the effects of the legislation is rather simple. The EMA and its PDCO are deeply convinced that all of their efforts and procedures are justified and will eventually translate into better medical care for children. The EU commission’s 2013 report about the pediatric regulation is a bit less enthusiastic and acknowledges that in 5 years no real breakthroughs have been achieved. However, it states that it is convinced that in 5 more years the situation will be clearer.20 Within the pharmaceutical industry, large companies have learned to live with the regulation, and top

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Clinical Therapeutics management has more urgent problems to deal with than problems with pediatric drug development. The times of easy blockbuster medicines are over; most companies have laid off thousands of employees. Within industry, the author has heard the EU pediatric requirements often described as ridiculous. At conferences, anecdotes and experiences are exchanged. Industry has seen other challenges in the past. Employees are assigned to deal with the operational challenges of PDCO negotiations; it is their job to perform whatever they are told to do. At present, the proposals from industry tend toward easier practicability of PIP details. Two major unknowns are academic science and the public in general. European academic pediatric clinicians by and large have still a positive perception of the EU regulation. They observed how in the past industry was not interested in them, but that has changed. Pediatric specialists are asked for their input by the pharmaceutical industry as well as for input into expert statements from the EMA. And the general public is happy that “something” is being done to force the pharmaceutical industry to do more for children. There are too many unknowns to predict how public opinion and academic perception will evolve over the next years. Cautiously worded concerns in special journals will take many years to reach the broader public. In the short term, institutional review boards/ethics committees will have to learn that many clinical studies triggered by EMA/PDCO negotiations are not the outcome of a dialogue between free partners, but rather have been “proposed” under duress by companies that are threatened with being put out of business if they do not make the right “proposals” and that not every clinical trial negotiated with the EMA is ethical just because it carries the EMA’s blessing. In the past, many ethics committee members perceived their role as simple—to protect children against “big, bad pharma.” Now ethics committees have to deal with the concept that they may have to protect children from PDCO-approved studies when they scrutinize clinical trials in children. The PDCO is already near the limits of its capacities with respect to the workload of PIP procedures. Partially due to the number of accepted PIPs also, the number of requests for modification is increasing. The traditional solution to this challenge would have been to ask for a bigger headcount and an increase in the size of the pediatric EMA department. The EMA

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might have to introduce fees to cover the increased cost of handling submissions and negotiation of PIPs, and industry would complain as usual. However, increasing fees and headcount are not easy in times of economic crisis. In the intermediate term, the detailed PIPs that block recruitment into pediatric oncology research organizations should be replaced, as proposed by Vassal et al,49 by a high-level early document without lengthy discussion of patient numbers, statistical assumptions, and further details of trials that are unlikely to ever be initiated anyway. Within such a new framework, it should be discussed whether or to what degree a committee of generalists like the PDCO can positively contribute to the delicate challenges of rare diseases. Orphan diseases are purposely excluded from mandatory US requirements. It would make a lot of sense to bar the PDCO from involvement in the development of drugs that target orphan diseases and exclusively or predominantly pediatric diseases. Companies that successfully manage the science and the mobilization of resources necessary to investigate pediatric-only or rare diseases have access to more drug- and disease-specific expertise than does the PDCO. These types of company efforts should be encouraged and rewarded in the European Union as they are in the United States. At present, such companies are punished and loaded with additional, often senseless requirements. The EMA committee that actually decides about registration of new drugs is CHMP.53 For drugs targeting orphan and predominantly pediatric diseases, discussions with CHMP should be sufficient, and the discussion round with the PDCO should simply be abolished. The degree to which common sense will prevail in the 2018 legislation will depend on the outcome of intensive discussions in the academic press, in academic and practice organizations, in learned societies, and in the general press. So far, it has been easier and cheaper for companies to simply pay lip service to PDCO requests, to give in and to initiate even those studies that senior management knows do not make sense and those that will never recruit the number of patients promised. The example of the company that lost 2 rounds of litigation at the EU Court of Justice has scared the industry.22,23 It is unpredictable whether another company will take the EMA to court. If this did happen and the court decided against the EMA, the company could sue for damages, which

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K. Rose would probably lead to more reasonable PIP requests. A better understanding of the causes and effects of exaggerated PIP requirements in the academic pediatric oncology community could certainly be useful to drive change. More representation of people with industry experience on the PDCO would be another way to improve PDCO discussions. In 2000, the European Union wanted, through its Lisbon agenda, to make the European Union by 2010 “the most competitive and dynamic knowledge-based economy in the world capable of sustainable economic growth with more and better jobs and greater social cohesion.”54 These objectives were not reached. More efficient EU pediatric drug development could help to achieve these goals. More drugs than ever are in development to treat orphan and rare diseases, which is the partial result of orphan drug legislation in the United States and the European Union. It would be desirable to see more effective initiatives that provide both room for economic growth and an environment that encourages, supports, and promotes, rather than inhibits, research in pediatric as well as adult cancers.

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ACKNOWLEDGMENTS The author would like to thank Dr. Peter Adamson, chairman of the US COG, for his high-level revision of the paper and his critical comments. He also thanks for the help provided by Dr. Phillip Walson, Editor Emeritus & Topic Editor-at-Large of Clinical Therapeutics during the submission process.

CONFLICTS OF INTEREST The author has indicated that he has no conflicts of interest with regard to the content of this article.

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K. Rose 43. Midostaurin PIP decision. http:// www.ema.europa.eu/docs/en_GB/ document_library/PIP_decision/WC 500101890.pdf. Accessed December 7, 2013. 44. Obinutuzumab PIP decision. http:// www.ema.europa.eu/docs/en_GB/ document_library/PIP_decision/WC 500142813.pdf. Accessed December 7, 2013. 45. Recombinant L-asparaginase PIP decision. http://www.ema.europa.eu/ docs/en_GB/document_library/PIP_ decision/WC500143701.pdf. Accessed December 7, 2013. 46. Volasertib PIP decision. http:// www.ema.europa.eu/docs/en_GB/ document_library/PIP_decision/WC 500142807.pdf. Accessed December 7, 2013. 47. Request for modification of an agreed paediatric investigation plan. http://www.ema.europa.eu/docs/ en_GB/document_library/Templa te_or_form/2010/03/WC5000754 28.pdf. Accessed December 7, 2013. 48. Application for Paediatric Investigation Plan/Waiver. http://www. ema.europa.eu/docs/en_GB/docu ment_library/Template_or_form/ 2010/03/WC500075428.pdf Accessed January 10 2014. 49. Vassal G, Zwaan CM, Ashley D. Improving cancer care for children and young people. III. New drugs for children and adolescents with cancer: the need for novel development pathways. Lancet Oncol. 2013;14: e117–e124. http://press.thelancet. com/childhoodcancer3.pdf. Accessed [date]. 50. Adamson PC. Unintended consequences of regulatory initiatives in childhood cancer drug development. JAMA Pediatr. 2013;167:886–887. 51. Innovative Therapies for Children with Cancer. http://www.itcc-con sortium.org/. Accessed December 7, 2013. 52. US Dept of Health and Human Services, Food and Drug Administration. Frequently asked questi-

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ons: breakthrough therapies. http:// www.fda.gov/regulatoryinformati on/legislation/federalfooddrugand cosmeticactfdcact/significantamend mentstothefdcact/fdasia/ucm3410 27.htm. Accessed December 7, 2013. 53. Committee for Medicinal Products for Human Use. http://www.ema. europa.eu/ema/index.jsp?curl=

pages/about_us/general/general_ content_000094.jsp. Accessed December 7, 2013. 54. Presidency Conclusions, Lisbon European Council 2010, 23 and 24 March 2000. http://www.con silium.europa.eu/uedocs/cms_data/ docs/pressdata/en/ec/00100-r1.en0. htm. Accessed December 7, 2013.

Address correspondence to: Klaus Rose, MD, MS, klausrose Consulting, Pediatric Drug Development and More, Aeussere Baselstrasse 308, 4125 Riehen, Switzerland. E-mail: [email protected]

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